ABSTRACT Atherosclerosis (ATH) is an inflammatory disease highly prevalent in the United States. A hallmark of the disease is the accumulation of macrophages/foam cells in the tunica intima of the arteries. The pathogenesis of ATH involves complex interactions between multiple cell types, tightly regulated by different molecular signaling pathways. We believe that Wnt5a plays a critical role in the pathogenesis of ATH therefore this proposal will provide new insights about the role(s) of Wnt5a in ATH that could be important to develop novel strategies for diagnosis and treatment. We have reported high levels of Wnt5a in atherosclerotic lesions. We also found transcriptional upregulation of Wnt5a in human monocyte derived macrophages and THP1 cells, a human monocytic cell line upon stimulation with oxidized low-density lipoprotein (oxLDL). More interestingly, we reported (1) a correlation between Wnt5a expression and histopathological severity of human atherosclerotic lesions, (2) variation of Wnt5a transcription in different areas of the plaque and (3) high levels Wnt5a in the serum of patients with atherosclerosis. Our long term goal is to characterize the molecular and cellular basis of ATH in order to develop novel, safe, and cost-effective strategies to combat this highly prevalent and deadly disease. The objectives of this application are two-fold: (1) to characterize the contribution of Wnt5a signaling in ATH plaque development and (2) determine the efficacy of targeting Wnt5a as a potential novel-therapeutic strategy. Our encouraging preliminary data, coupled with data from other researchers, has led us to hypothesize that ATH results, in part, from oxLDL activation of Wnt5a signaling in macrophages via Frizzled5/Ror2 which triggers foam cell formation and that abrogation of Wnt5a signaling using UM206 can prevent and/or delay the progression of ATH. We will test this hypothesis by accomplishing the following specific aims: Specific Aim 1. To define the role of Wnt5a signaling in atherosclerosis and to determine the efficacy of targeting Wnt5a as a potential novel therapeutic strategy. Specific Aim 2. To develop a targeted liposomal system to deliver Wnt5a inhibitory compounds by targeting molecules expressed in atherosclerotic lesions. The outcomes from this proposal will provide an important positive impact (1) on the therapeutic treatment and/or prevention of ATH by offering a potentially novel therapeutic modality (2) on advancing our knowledge and understanding of the complex pathological mechanisms that underline ATH, and (3) on the training of graduate and undergraduate students who aspire to be involved in translational and basic research.